Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action
An 85-year-old, 60-kg woman with a serum creatinine of 1.8 mg/dL has atrial fibrillation. A decision has been made to use digoxin to control the rapid heart rate. The target concentration of digoxin for the treatment of atrial fibrillation is 2 ng/mL. Tablets of digoxin contain 62.5 micrograms and 250 micrograms (mcg). What mainte-nance dose would you recommend?
The goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects. When a medicine has been selected for a patient, the clinician must determine the dose that most closely achieves this goal. A rational approach to this objective combines the principles of pharmacokinetics with pharmacody-namics to clarify the dose-effect relationship (Figure 3–1). Pharmacodynamics governs the concentration-effect part of the interaction, whereas pharmacokinetics deals with the dose-concentration part (Holford & Sheiner, 1981). The pharma-cokinetic processes of absorption, distribution, and elimination determine how rapidly and for how long the drug will appear at the target organ. The pharmacodynamic concepts of maximum response and sensitivity determine the magnitude of the effect at a particular concentration (see Emax and C50,; C50 is also known as EC50).Figure 3–1 illustrates a fundamental hypothesis of pharmacol-ogy, namely, that a relationship exists between a beneficial or toxic effect of a drug and the concentration of the drug. This hypothesis has been documented for many drugs, as indicated by the Target Concentrations and Toxic Concentrations columns in Table 3–1. The apparent lack of such a relationship for some drugs does not weaken the basic hypothesis but points to the need to consider the time course of concentration at the actual site of pharmacologic effect .
Knowing the relationship between dose, drug concentration, and effects allows the clinician to take into account the various pathologic and physiologic features of a particular patient that make him or her different from the average individual in respond-ing to a drug. The importance of pharmacokinetics and pharma-codynamics in patient care thus rests upon the improvement in therapeutic benefit and reduction in toxicity that can be achieved by application of these principles.